Tumor microvasculature is a therapeutic target in the treatment of cancer. The overall hypothesis of this translational research is that the cytotoxic effects of ionizing radiation on the tumor microvascular endothelium are attenuated by activation of the PI3K/Akt signaling pathway. We have found that ionizing radiation induces the activation of PI3K/Akt, which in turn regulates endothelial cell viability during treatment with radiotherapy. Inhibition of this signaling pathway enhances the cytotoxic effects of radiation in tumor vascular endothelium resulting in enhanced tumor control. The goals of the proposed research are to study the mechanisms by which ionizing radiation activates the PI3K/Akt signaling pathway. This research will lead to potential new molecular targets for therapy. Our overall goal is to bring this therapeutic strategy into clinical trials. We will, therefore, study inhibitors of this signal transduction pathway that are pipeline compounds for clinical trials. The proposed specific aims combine both basic and translational research with the intention of developing new strategies for the treatment of cancer. We hypothesize that radiation-induced activation of PI3K/Akt signaling in tumor microvasculature is initiated through 3 potential mechanisms: 1) ligand-mediated RTK activation; 2) direct RTK activation by radiation; and/or 3) inactivation of protein tyrosine phosphotases. These mechanisms are not mutually exclusive and may each contribute toward amplification of the PI3K/Akt signaling. In Specific Aim 1, we will determine the role of receptor tyrosine kinases in radiation-induced activation of the PI3K/Akt pathway. In Specific Aim 2, we will determine the role of protein tyrosine phosphotase (PTP) inactivation in radiation-induced activation of the PI3K/Akt signaling pathway. In Specific Aim 3, we will determine the biologically active dose of TKIs that enhance the cytotoxic effects of radiation on tumor vascular endothelium. We will identify molecular targets to improve local and regional control of cancers such as malignant gliomas and head and neck cancer. The importance of this study is that new molecular targets for radiation sensitization will be identified. Furthermore, we will characterize pipeline TKIs for clinical protocol development. The significance of this investigation is that quality of life; organ preservation and cure rates can be improved by enhancing the cytotoxic effects of localized irradiation through the use of tyrosine kinase inhibitors.